The effects of erythropoietin are mediated via the erythropoietin receptor. The envelope protein of Friend leukemia virus, gp55, specifically binds the Epo receptor in an infected erythroblast and activates constitutive Epo receptor signaling. Two similar gp55s, FVA and FVP, induce differences in erythroid proliferation and transformation in vivo. FVP gp55 induces polycythemia during the first stage of Friend erythroleukemia which is Epo-independent, whereas FVA gp55 induces an anemia that is Epo-dependent. During stage II of Friend disease, subsequent genetic alterations develop, resulting in an emergence of malignant erythroblasts and frank erythroleukemia. The specific aims of this proposal are: 1) to identify and compare FVP- and FVA-induced changes in Epo receptor-mediated signaling and relate these changes to their differential growth and transformation properties; and 2) to compare structure/function effects of FVA and FVP mutants on Epo receptor binding and activation of erythropoietin receptor signaling, and relate these to changes in growth and transformation.